IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor responsible for activation of B-lymphatic cells (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokine that influences the function of various cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 has been reported to induce the maturation of T lymphatic cells (Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258).
IL-6 propagates its biological activity through two proteins on the cell. One is a ligand-binding protein, IL-6 receptor, with a molecular weight of about 80 kD to which IL-6 binds (Taga T. et al., J. Exp. Med. (1987) 166, 967-981; Yamasaki, K. et al., Science (1987) 241, 825-828). IL-6 receptor exists not only in a membrane-bound form that penetrates and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region.
The other is non-ligand-binding membrane-bound protein gp130 with a molecular weight of about 130 kD that takes part in signal transduction. IL-6 and IL-6 receptor form an IL-6/IL-6 receptor complex, to which gp130 is bound, and thereby the biological activity of IL-6 is propagated into the cell (Taga et al., Cell (1989) 58, 573-581).
IL-6 antagonists are substances that inhibit the transduction of IL-6 biological activities. Up to now, there have been known antibodies to IL-6 (anti-IL-6 antibodies), antibodies to IL-6 receptor (anti-IL-6 receptor antibodies), antibodies to gp130 (anti-gp130 antibodies), reshaped IL-6, IL-6 or IL-6 receptor partial peptides, and the like.
Antibodies to IL-6 receptor have been described in a number of reports (Novick D. et al., Hybridoma (1991) 10, 137-146; Huang, Y. W. et al., Hybridoma (1993) 12, 621-630; International Patent Application WO 95-09873; French Patent Application FR 2694767; U.S. Pat. No. 5,216,128). A humanized PM-1 antibody was obtained by implanting the complementarity determining region (CDR) of a mouse antibody PM-1 (Hirata et al., J. Immunology (1989), one of anti-IL-6 receptor antibodies, 143, 2900-2906) into a human antibody (International Patent Application WO 92-19759).
Chronic arthritides diseases of childhood are diseases comprising mainly chronic arthritis that develops at less than 16 years of age and is the most prevalent disease among the collagen diseases that develop in children. Unlike rheumatoid arthritis (RA) in adults, they are not considered to be a homogeneous disease and have a variety of disease types, and therefore they tend to be dealt with as a disease entity different from rheumatoid arthritis in adults.
As the name of chronic arthritides diseases of childhood, “juvenile rheumatoid arthritis (JRA)” has been used in Japan according to the diagnostic criteria in the United States, whereas in Europe the term “juvenile chronic arthritis (JCA)” is mainly used. Recently, terms such as idiopathic chronic arthritis (ICA) and juvenile idiopathic arthritis (JIA) have been used.
The disease types of chronic arthritides diseases of childhood have been categorized in various ways. According to the American College of Rheumatology (ACR), they are divided, as arthritic diseases that develop in children less than 16 years old and persist for six weeks or longer, into three disease types: 1) systemic onset JRA, 2) polyarticular, 3) pauciarticular (ARA classification) (JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association Arthritis Rheum 20 (Suppl): 195, 1977). In Europe, the European League Against Rheumatism (EULAR) has made a classification that states that, though it differs from the above ARA classification in that the duration of arthritis is three months or more and arthritis due to psoriasis, ankylosing spondylitis etc. has been excluded, the three disease types are similar (Bulletin 4, Nomenclature and classification of Arthritis in Children. Basel, National Zeitung AG, 1977).
Recently, a revision of the classification has been attempted, and the International League of Associations for Rheumatology (ILAR) proposed in 1995 a classification plan of Idiopathic Arthritides of Childhood (Fink C W, Proposal for the development of classification criteria for idiopathic arthritides of childhood. J. Rheumatol., 22: 1566 (1995)), and in 1997 the revision was proposed as an ILAR plan (Southwood T R, Classifying childhood arthritis, Ann. Rheum. Dis. 56: 79 (1997)). This classification provides division into: 1) systemic arthritis, 2) polyarthritis RF positive, 3) polyarthritis RF negative, 4) oligoarthritis, 5) extended oligoarthritis, 6) enthesitis related arthritis, 7) psoriatic arthritis, and 8) others.
Furthermore, the present inventors have proposed a method of classifying chronic arthritides diseases of childhood into:
1) Primary Chronic Arthritides of Childhood
(1) SPRASH Syndrome (SPRASH: Spiking Fever, Pericarditis, Rash, Arthritis, Splenomegaly, Hepatomegaly)
Starts with relaxation heat and efflorescence, and serositis and hepatomegaly are observed with concomitant onset of simultaneous or delayed arthritis, but at times arthritis may not be observed.
(2) Idiopathic Chronic Arthritides of Childhood
No underlying diseases are present, and arthritis is the key pathology.                a) rheumatoid factor (RF)-positive type        b) anti-nuclear antibody (ANA)-positive type        c) RF/ANA-negative type        
2) Secondary Chronic Arthritides of Childhood
Genetic or nongenetic original diseases are accompanied by arthritis (Shunpei Yokota, “Advances in recent therapeutic methods for chronic arthritides diseases of childhood”, Rheumatism, 39: 860 (1999)).
It has been reported that various cytokines are involved in chronic arthritides diseases of childhood. In particular, it is thought that imbalance in inflammatory cytokines IL-1, IL-6, IL-12 and TNF-α, and anti-inflammatory cytokines IL-1ra (IL-1 receptor antagonist), IL-10, IL-13, sTNFR (soluble TNF receptor) is associated with the disease.
For the treatment of chronic arthritides diseases of childhood, nonsteroidal anti-inflammatory drugs, corticosteroids, antirheumatic drugs (gold compounds etc.), immunosuppressants, methotrexate (MTX etc.) have been used. However, as the therapeutic effects differ with the patients, the development of more effective therapeutic regimens is being awaited.
Still's disease, first described by the British pediatrician Dr. Still in 1897, was reported to have a clinical picture clearly different from that of rheumatoid arthritis in adults and is a disease seen in children to adults (especially in adolescence and the main symptoms include fever, erythema, arthritis, serositis and the like. Among them, adult-onset type is designated as adult onset Still's disease. In Still's disease, rheumatoid factor is usually negative.
In children, Still's disease is another name of the systemic type of juvenile rheumatoid arthritis (juvenile rheumatoid arthritis (JRA), JCA (juvenile chronic arthritis), juvenile idiopathic arthritis (JIA)) which is a chronic arthritis developing in children at less than 16 years old. For the causes of Still's disease, environmental factors such as a virus, host factors such as HLA, and immunological abnormalities have been reported, but the etiology is still obscure.
Still's disease in adults and that in children are considered to be almost the same disease, though there are minor differences in clinical feature in addition to the age when the disease develops. Still's disease in children refers to JRA of the systemic type as described above. However, JRA and rheumatoid arthritis (RA) in adults are clinically different in many ways and are dealt with as different diseases, and therefore Still's disease in adults is often dealt with as an independent disease entity among the rheumatic diseases.
As diagnostic criteria for Still's disease in adults, there have been known those by Yamaguchi (Journal of Rheumatology 19(3): 424-30, 1992), Reginato (Seminars in Arthritis & Rheumatism 17(1): 39-57, 1987), Cush (Rheumatology Grand Rounds, University of Pittsburgh Medical Center; Jan. 30, 1984), Goldman (Southern Medical Journal 73: 555-563, 1980) and the like.
On the relationship between Still's disease and cytokines, association with cytokines such as IL-1, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, TNF-α, and IFN-γ has been reported, and among them, inflammatory cytokines such as IL-1, IL-6, TNF-α, and IFN-γ have been implicated in the pathology of Still's disease.
With respect to IL-6, de Benedetti et al. reported that serum levels of IL-6 are elevated in Still's disease in children (Arthritis Rheum. 34: 1158, 1991), and that a large amount of IL-6/soluble IL-6 receptor (sIL-6R) complex is present in the serum of patients with Still's disease in children and a correlation can be seen between this complex level and CRP values (J. Clin. Invest. 93: 2114, 1994). Furthermore, Rooney et al. have reported that plasma levels of IL-6 and TNF-α are elevated in patients with Still's disease in children (Br. J. Rheumatol. 34: 454, 1995).
As a method of treating Still's disease, nonsteroidal anti-inflammatory drugs, corticosteroids, antirheumatic drugs (gold compounds etc.), immunosuppressants, gamma globulin formulations, methotrexate (MTX etc.) have been used. However, as the therapeutic effects differ with the patients, the development of more effective therapeutic regimens is being sought after.